Development of Tumor-Targeted Pegylated Colloidal Gold *

描述(由申请人提供)： 目前，可切除实体肿瘤的一线治疗最常见的是手术，然后是化疗和/或放射治疗。不幸的是，这种策略常常因为复发或转移性疾病而失败。为了改变这种模式，新的癌症治疗方法必须提供多方面的治疗方法，以在手术切除之前摧毁实体肿瘤中存在的异质肿瘤细胞群。目前的提案寻求在聚乙二醇化的胶体金纳米颗粒平台(CAU)上开发这种肿瘤靶向纳米疗法，旨在将有效的抗癌药物组合输送到实体肿瘤。开发的第一种药物(命名为CyT-0691)主动靶向并隔离实体肿瘤中的人肿瘤坏死因子α(TNF)，同时避免网状内皮系统(RES)的摄取和清除。该药物由肿瘤坏死因子和硫代化聚乙二醇(一种RES避免分子)组成，作为单独的分子共价结合到26纳米CAU纳米颗粒的表面。这项提议寻求使用与肿瘤坏死因子结合的聚乙二醇化的CAU纳米颗粒作为一系列新的癌症联合纳米疗法的核心。这些新的纳米疗法将组装在聚乙二醇化的CAU的单个颗粒上，旨在提供肿瘤坏死因子和与肿瘤坏死因子对实体肿瘤的已知作用相协同的第二种治疗方法。拟议的CAU纳米药物的多价性将要求我们进一步了解目前对纳米颗粒平台以及假定的治疗药物与CAU纳米颗粒表面的相互作用的理解。为了迎接这一挑战，Cytlmmune组建了一个多学科的专家团队，以解决使聚乙二醇化的CAU纳米颗粒成为开发肿瘤靶向纳米疗法的平台技术的基本和应用挑战。每个小组成员的专业知识将用于解决CAU纳米颗粒的表面结合化学、CAU结合药物的合成和表征以及每个新的聚乙二醇化CAU纳米颗粒载体的生物表征等具体问题。Cytlmmune的合作者包括弗吉尼亚理工大学的David Kingson博士、Clarkson大学的Dan Goia博士、卡内基研究所地球物理实验室的Viktor Struzhkin博士和Andrew Steele博士，以及布法罗大学化学系的Paras Prasad博士和Haridas Pudavar博士。

DESCRIPTION (provided by applicant): Currently, first-line treatment of resectable solid tumors most commonly involves surgery followed by a regimen of chemotherapy and/or radiation. Unfortunately, this strategy often fails because of recurrent or metastatic disease. To change this paradigm, new cancer therapies must deliver multifaceted therapeutics to destroy the heterogeneous population of tumor cells present within solid tumors prior to surgical removal. The current proposal seeks to develop such tumor-targeted nanotherapies on a pegylated colloidal gold nanoparticle platform (cAu) designed to deliver a combination of potent anti-cancer drugs to solid tumors. The first drug developed (designated CYT-0691) actively targets and sequesters human tumor necrosis factor alpha (TNF) in solid tumors while avoiding uptake and clearance by the reticuloendothelial system (RES). The drug is comprised of TNF and thiolated polyethylene glycol (an RES avoidance molecule) that are covalently bound, as individual molecules, to the surface of 26 nm cAu nanoparticles. This proposal seeks to use TNF bound to pegylated cAu nanoparticles as the core of a family of new combinational cancer nanotherapies. These new nanotherapies will be assembled on a single particle of pegylated cAu and are designed to deliver both TNF and a second therapeutic that synergizes with the known actions of TNF on solid tumors. The multivalent nature of the proposed cAu nanodrugs will require us to further our current understanding of the nanoparticle platform and the interaction of the putative therapeutics with the cAu nanoparticle's surface. To meet this challenge, Cytlmmune has assembled a multidisciplinary team of experts to address the basic and applied challenges of making pegylated cAu nanoparticles a platform technology for developing tumor-targeted nanotherapeutics. The expertise of each team member will be brought to bear in addressing specific issues of surface binding chemistries to cAu nanoparticles, the synthesis and characterization of the cAu bound drugs, and the biologic characterization of each new pegylated cAu nanoparticle vector. Cytlmmune's collaborators include Dr. David Kingson of Virginia Tech., Dr. Dan Goia from Clarkson University, Drs. Viktor Struzhkin and Andrew Steele of the Geophysical Laboratory of the Carnegie Institute, and Drs. Paras Prasad and Haridas Pudavar of the Department of Chemistry at the University of Buffalo.